Cellular Sources Of Neuregulin 1 (NRG1) Regulating Neural Activity And Behavior

调节神经活动和行为的神经调节蛋白 1 (NRG1) 的细胞来源

• 批准号: 9196715
• 负责人: CLARE M BERGSON
• 金额: $ 19万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9196715
• 关键词: Affect; Astrocytes; Attenuated; Behavior; Brain; Breeding; Cell physiology; Cells; Chimeric Proteins; Drug Design; Enterobacteria phage P1 Cre recombinase; Epilepsy; Epileptogenesis; Equilibrium; ErbB4 gene; Estrogen Receptors; Exploratory Behavior; Family; Genes; Glial Fibrillary Acidic Protein; Glutamate Decarboxylase; Goals; Hippocampus (Brain); Hyperactive behavior; Interneurons; Knockout Mice; Knowledge; Learning; LoxP-flanked allele; Measures; Memory; Mus; Neuregulin 1; Neurons; Outcome; Pain; Parvalbumins; Patients; Performance; Physiologic pulse; Play; Population; Process; RNA Interference; Receptor Protein-Tyrosine Kinases; Role; Schizophrenia; Seizures; Short-Term Memory; Signal Transduction; Slice; Societies; Source; Synapses; Synaptic Transmission; Synaptic plasticity; Tamoxifen; Testing; cell type; cognitive function; excitatory neuron; executive function; gamma-Aminobutyric Acid; improved; information processing; insight; knowledge base; neuromechanism; neurotrophic factor; receptor; relating to nervous system; therapeutic target; transmission process

Project Summary Schizophrenia (Sz) affects 1% of the population worldwide and places a costly and painful burden on patients, their families and society. Currently there are no treatments available to effectively rehabilitate Sz patients. The neurotrophic factor Neuregulin 1 (NRG1) is a promising therapeutic target because the gene is associated with Sz in various populations, and NRG1 levels are altered in Sz. NRG1 stimulates the ErbB family of tyrosine kinase receptors, including ErbB4, which is associated with Sz. NRG1 signaling via ErbB4 receptors expressed in parvalbumin (PV)-positive interneurons promotes neural processes important for executive functions which are impaired in Sz. A critical barrier to progress in improving treatment of Sz is a lack of understanding of whether the cells, which produce the NRG1 resulting in release of GABA or stimulation of gamma oscillations, also supply the NRG1 involved in suppression of LTP or seizure activity. Our goal is to improve the treatment of Sz by obtaining the information and understanding needed for designing drugs capable of quelling seizures without inhibiting neural mechanisms involved in learning and memory. Our central hypothesis is that different cellular sources of NRG1 differentially and selectively impact synaptic transmission, network activity and behavior, and that these unique cellular functions are potential mechanisms by which NRG1 could suppress seizures as well as promote network activity important for higher brain functions. Our objectives are to 1) determine the cell-type specific roles of neuronal and astrocytic NRG1 in GABA transmission, gamma oscillations, LTP, epileptogenesis, and Sz-relevant mouse behaviors and 2) provide clarification of the cellular sources of NRG1 involved in mechanisms regulating excitatory-inhibitory balance within local circuits, and facilitating transfer of information from hippocampus to cortex. Our expected outcomes include 1) knowledge of the cellular origins of NRG1 engaged during different states of synaptic and network activity, 2) improved understanding of the neuronal and astrocytic mechanisms underpinning NRG1 activation of ErbB4, and 3) new insights into the specific roles played by astrocytic and neuronal NRG1 in behaviors requiring cognitive functions often impaired in Sz. The impact of our findings will provide a stronger rationale for therapeutically targeting NRG1 during pathological conditions, as well as an improved knowledge base, which is needed for designing drugs capable of quelling seizures without inhibiting neural mechanisms involved in learning and memory. Aim 1 will test the hypothesis that NRG1 derived from principal neurons, interneurons and astrocytes differentially regulates excitatory and inhibitory synaptic transmission. Aim 2 will test the hypothesis that NRG1 derived from these three different cell types differentially regulate Sz-relevant behaviors.

项目摘要 精神分裂症（Sz）影响全球1%的人口，并给患者带来昂贵和痛苦的负担， 家庭和社会。目前还没有有效的治疗方法来恢复Sz患者。的 神经营养因子Neuregulin 1（NRG 1）是一个有前途的治疗靶点，因为该基因与 Sz在各种人群中，NRG 1水平在Sz改变。NRG 1刺激酪氨酸的ErbB家族 激酶受体，包括ErbB 4，其与Sz相关。通过ErbB 4受体表达的NRG 1信号传导 在小清蛋白（PV）阳性中间神经元中，促进对执行功能重要的神经过程， 在Sz中受损。改善Sz治疗进展的一个关键障碍是缺乏对以下方面的了解： 无论是产生NRG 1导致GABA释放或刺激γ振荡的细胞， 还提供参与抑制LTP或癫痫发作活动的NRG 1。我们的目标是改善治疗 通过获得设计能够平息癫痫发作的药物所需的信息和理解， 而不抑制参与学习和记忆的神经机制。我们的核心假设是， NRG 1的不同细胞来源差异性和选择性地影响突触传递、网络活动 这些独特的细胞功能是NRG 1可以 抑制癫痫发作以及促进对高级脑功能重要网络活动。我们的目标是 1）确定神经元和星形胶质细胞NRG 1在GABA传递中的细胞类型特异性作用，γ 振荡，LTP，癫痫发生和SZ相关的小鼠行为和2）提供细胞的澄清， 参与调节局部回路内兴奋-抑制平衡机制的NRG 1来源，以及 促进信息从海马体到皮层的传递。我们的预期成果包括：（1）知识 NRG 1的细胞起源在突触和网络活动的不同状态下参与，2）改善 理解支持ErbB 4的NRG 1激活的神经元和星形胶质细胞机制，以及3）新的 深入了解星形胶质细胞和神经元NRG 1在需要认知的行为中所起的特定作用， 功能经常受损的Sz。我们的研究结果的影响将为治疗提供更有力的理由。 在病理条件下靶向NRG 1，以及改进的知识基础，这是必要的， 设计能够在不抑制参与学习的神经机制的情况下平息癫痫发作的药物， 记忆目的1验证NRG 1来源于主神经元、中间神经元和星形胶质细胞的假说 差异调节兴奋性和抑制性突触传递。目标2将检验NRG 1 来源于这三种不同细胞类型的细胞差异调节SZ相关行为。